RU2807183C2 - Solid compositions containing glp-1 agonist and n-(8-(2-hydroxybenzoyl)amino)caprylic acid salt and lubricant - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: pharmaceutical compositions containing a GLP-1 peptide and an N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt.

EFFECT: method for treating diabetes mellitus and/or obesity in a subject.

10 cl, 4 ex, 8 tbl, 2 dwg

Description

Field of technology to which the invention relates

The present invention relates to solid compositions containing a GLP-1 agonist and an N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt, a method for their preparation and their use in medicine.

Incorporating a sequence listing by reference

The sequence listing entitled “SEQUENCE LISTING” is 4 kilobytes in size and was created on January 23, 2017, and is incorporated herein by reference.

State of the art

Human GLP-1 and its analogues have low oral bioavailability. Following oral administration, exposure and bioavailability of human GLP-1 and its analogues are very low. Thus, human GLP-1 (and its analogues) can be detected in plasma after oral administration only if formulated with certain absorption enhancers in a specific amount.

Steinert et al. (Am J Clin Nutr, Oct 2010; 92: 810 - 817) disclose the oral administration of a tablet containing GLP-1(7-36)-amide and 150 mg sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC ).

WO 2010/020978 discloses an oral pharmaceutical composition containing protein and N-(8-[2-hydroxybenzoyl)amino)caprylate (SNAC). Patent applications disclosing GLP-1 analogue oral dosage forms containing N-(8-(2-hydroxybenzoyl)-amino)caprylate salt include WO2012/080471, WO2013/189988, WO2013/139694, WO2013/139695 and WO2014 /177683.

Despite these results, it is still possible to obtain a further optimized pharmaceutical composition for oral administration of a GLP-1 agonist, such as a GLP-1 analog containing a substituent.

Short description

The present invention relates to a composition containing a GLP-1 agonist and an absorption enhancer or delivery vehicle. In one embodiment, the composition in accordance with the present invention contains a very high content of delivery vehicle and a minimal content of additional excipients described herein below. The presented compositions demonstrate accelerated absorption, which allows for rapid and effective absorption of the active pharmaceutical ingredient.

Oral administration of therapeutic peptides is difficult due to the rapid degradation of such peptides in the gastrointestinal tract. Disclosed herein are pharmaceutical compositions that provide acceleration of absorption of a GLP-1 agonist within 15 to 30 minutes after administration and thereby increase exposure of the GLP-1 agonist when administered orally. The present inventors have surprisingly discovered that plasma exposure of GLP-1 agonists is increased when formulations are formulated with a very high absorption enhancer content and minimal content of any additional excipients.

In one aspect, the present invention relates to a composition wherein the mass fraction of the delivery vehicle relative to the composition as a whole or, in particular, relative to the remaining excipients of the composition is very high.

In one embodiment, the present invention provides a pharmaceutical composition comprising a GLP-1 agonist, a delivery vehicle and/or an absorption enhancer, such as SNAC, wherein the delivery vehicle/absorption enhancer comprises at least 90%, such as at least at least 95% w/w of the excipients of the composition.

In one embodiment, the present invention provides a pharmaceutical composition comprising a GLP-1 agonist, a delivery vehicle and/or an absorption enhancer, such as SNAC, wherein the delivery vehicle/absorption enhancer comprises at least 90% w/w of the composition.

In additional embodiments, the composition further comprises a lubricant.

In one aspect, the present invention relates to a method for preparing a pharmaceutical composition described herein, such as a method comprising the steps of:

a) granulating a mixture containing a delivery vehicle, a GLP-1 agonist and optionally a lubricant, and

b) compressing the granulate obtained in step a) into tablets and optionally adding additional lubricant to the granulate before compression.

In a further aspect, the present invention relates to a composition or granule as defined herein for use in medicine, such as for the treatment of diabetes mellitus or obesity, wherein the composition is administered orally.

In a further aspect, the present invention relates to a method of treating diabetes mellitus or obesity comprising administering a composition as defined herein to a patient in need thereof, wherein the composition is a tablet and is administered orally.

Brief description of graphic materials

In fig. Figure 1 shows the rapid dissolution of A1 compared to reference A.

In fig. 2 shows the increase in dose-adjusted exposure of analogues A, B and C, formulated in accordance with the present invention, after oral administration of the tablet to beagle dogs. Data are given as average values. Compositions A1, B1 and C1 all showed increased dose-adjusted exposure compared to the reference compositions.

Description

An aspect of the present invention relates to a composition comprising a GLP-1 agonist and an absorption enhancer or delivery vehicle. The composition may be in a form suitable for oral administration, such as a tablet, sachet or capsule. In one embodiment, the composition is an oral composition or a pharmaceutical composition, such as an oral pharmaceutical composition.

In one embodiment, the composition in accordance with the present invention contains a high content of delivery vehicle and a minimum content of additional excipients described herein below. The presented compositions demonstrate accelerated dissolution and absorption, which allows for rapid and effective absorption of the active pharmaceutical ingredient.

GLP-1

As used herein, the term “GLP-1 agonist” refers to a compound that fully or partially activates the human GLP-1 receptor. Thus, this term is equivalent to the term “GLP-1 receptor agonist” as used elsewhere. The term GLP-1 agonist, as well as the specific GLP-1 agonists described herein, is intended to include their salt forms.

It follows that a GLP-1 agonist must exhibit “GLP-1 activity,” which means the ability of the compound, i.e. a GLP-1 analogue or a compound containing a GLP-1 analogue, bind to the GLP-1 receptor and initiate a signal transduction pathway leading to insulinotropic action or other physiological effects known in the art. In some embodiments, a "GLP-1 agonist" binds to a GLP-1 receptor, e.g., with an affinity constant ( _KD ), or activates the receptor with an potency ( _EC50 ) of less than 1 μM, e.g., less than 100 nM, as measured using methods known in the art (see, for example, WO 98/08871), and exhibits insulinotropic activity, where insulinotropic activity can be measured in in vivo or in vitro assays known to those of ordinary skill in the art. For example, a GLP-1 agonist can be administered to an animal with elevated blood glucose (eg, obtained using an intravenous glucose tolerance test (IVGTT). One skilled in the art will be able to determine the appropriate dose of glucose and the appropriate blood sample collection schedule for IVGTT , for example, depending on the biological species of the animal) and measure the concentration of insulin in the blood plasma over time.

Suitable assays have been described, for example, in WO2015/155151.

The term half-maximal effective concentration (EC ₅₀ ) generally refers to the concentration that induces a response midway between baseline and maximum, based on a dose-response curve. EC ₅₀ is used as a measure of the potency of a compound and is the concentration at which 50% of its maximum effect is observed. Due to the albumin-binding effects of the substituent GLP-1 agonists described herein, it is important to note whether the assay includes human serum albumin or not.

In vitro, GLP-1 agonist potency can be determined as described in 2015/155151, example 29 (HSA-free assay) and determined by EC50. The lower the EC ₅₀ value, the higher the efficiency. In one embodiment, the determined potency (EC50) (non-HSA assay) is 5-1000 pM, such as 10-750 pM, 10-500 pM, or 10-200 pM. In one embodiment, the EC50 (non-HSA assay) is no more than 500 pM, such as no more than 300 pM, such as no more than 200 pM.

In one embodiment, the EC50 (non-HSA assay) is comparable to that of human GLP-1(7-37).

In one embodiment, the EC50 (assay without HSA) is no more than 50 pM. In such a further embodiment, the EC50 is no more than 40 pM, such as no more than 30 pM, such as no more than 20 pM, such as no more than 10 pM. In one embodiment, the EC50 is approximately 10 pM.

If necessary, the fold change relative to a known GLP-1 receptor agonist can be calculated as EC50 (test analogue)/EC50 (known analogue), and if this ratio is 0.5-1.5 or 0.8-1.2, it is considered that the efficiencies are equivalent.

In one embodiment, the efficacy, EC50 (non-HSA assay), is equivalent to that of liraglutide.

In one embodiment, the potency, EC50 (non-HSA assay), is equivalent to that of semaglutide.

In one embodiment, the potency, EC50 (non-HSA assay), is equivalent to that of Compound B.

In one embodiment, the potency, EC50 (non-HSA assay), is equivalent to that of Compound C.

In some embodiments, the GLP-1 agonist is a GLP-1 analog, optionally containing a single substituent. The term "analog" as used herein in relation to a GLP-1 peptide (hereinafter "peptide") means a peptide wherein at least one amino acid residue of the peptide has been replaced by another amino acid residue, and/or wherein at least one an amino acid residue has been removed from the peptide, and/or where at least one amino acid residue has been added to the peptide, and/or where at least one amino acid residue of the peptide has been modified. Such addition or removal of amino acid residues may occur at the N-terminus of the peptide and/or at the C-terminus of the peptide. In some embodiments, a simple nomenclature is used to describe a GLP-1 agonist, e.g., [Aib8]GLP-1(7-37) refers to a GLP-1(7-37) analogue in which the naturally occurring Ala at position 8 has been replaced by Aib . In some embodiments, the GLP-1 agonist contains a maximum of twelve, such as a maximum of 10, 8, or 6 amino acids that have been changed, such as by substitution, deletion, insertion, and/or modification, such as compared to GLP-1( 7-37). In some embodiments, the analog contains up to 10 substitutions, deletions, additions and/or insertions, such as up to 9 substitutions, deletions, additions and/or insertions, up to 8 substitutions, deletions, additions and/or insertions, up to 7 substitutions, deletions, additions and/or insertions, up to 6 substitutions, deletions, additions and/or insertions, up to 5 substitutions, deletions, additions and/or insertions, up to 4 substitutions, deletions, additions and/or insertions or up to 3 substitutions, deletions, additions and/or insertions, for example, compared to GLP-1(7-37). Unless otherwise noted, GLP-1 contains only L-amino acids.

In some embodiments, the term “GLP-1 analog” or “GLP-1 analog” as used herein refers to a peptide or compound that is a variant of human glucagon-like peptide-1 (GLP-1(7-37)). GLP-1(7-37) has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In some embodiments, the term “variant” refers to a compound that contains one or more amino acid substitutions, deletions, additions, and/or insertions.

In one embodiment, the GLP-1 agonist has at least 60%, 65%, 70%, 80%, or 90% sequence identity to GLP-1(7-37) over the entire length of GLP-1(7-37). As an example of a method for determining the sequence identity of two analogues, the two peptides [Aib8]GLP-1(7-37) and GLP-1(7-37) were aligned. The sequence identity of [Aib8]GLP-1(7-37) to GLP-1(7-37) is reported as the number of aligned identical residues minus the number of divergent residues divided by the total number of residues in GLP-1(7-37). Accordingly, in this example the sequence identity is (31-1)/31.

In one embodiment, the GLP-1 agonist has an amide group at the C-terminus.

In some embodiments, the GLP-1 agonist is GLP-1(7-37) or GLP-1(7-36) amide. In some embodiments, the GLP-1 agonist is exendin-4, the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID No: 2).

To prolong the effect of the GLP-1 agonist, it is preferable that the GLP-1 agonist has an extended half-life. The half-life can be determined using a method known in the art and in a suitable model, such as male Sprague Dawley rats or minipigs, as described in WO2012/140117.

In one embodiment, the GLP-1 agonist of the present invention has a half-life in the minipig greater than 24 hours. In one embodiment, the GLP-1 agonist of the present invention has a half-life in a minipig of greater than 30 hours, such as greater than 36 hours, such as greater than 42 hours, such as greater than 48 hours, such as for example, more than 54 hours or, for example, more than 60 hours.

In some embodiments, the GLP-1 agonist contains a single substituent that is covalently attached to the peptide. In some embodiments, the substituent is a fatty acid or dibasic fatty acid. In some embodiments, the substituent is a C16, C18, or C20 fatty acid. In some embodiments, the substituent is a dibasic C16, C18, or C20 fatty acid.

In some embodiments, the substituent provides formula (X):

(X), where n is at least 13, for example, n is 13, 14, 15, 16, 17, 18, or 19. In some embodiments, the substituent is of the formula (X), where n is in the range of 13 to 19 , such as in the range from 13 to 17. In some embodiments, the substituent is of formula (X), where n is 13, 15, or 17. In some embodiments, the substituent is of formula (X), where n is 13. In some embodiments, the substituent is provides formula (X), where n is 15. In some embodiments, the substituent provides formula (X), where n is 17.

In some embodiments, the substituent provides formula (XIa):

HOOC-(C ₆ H ₄ )-O-(CH ₂ ) _m -CO-* (XIa), where m is an integer in the range 6-14.

In some embodiments, the substituent provides formula (XIb):

(XIb), where the carboxy group is at position 2, 3 or 4 of the group (C ₆ H ₄ ) and where m is an integer in the range 8-11.

In some embodiments, the substituent is of formula (XIa) or formula (XIb), wherein m is in the range of 6 to 14, such as in the range of 8 to 11. In some embodiments, the substituent is of formula (XIa) or formula ( XIb), where m is 8, 10, or 12. In some embodiments, the substituent is formula (XIa) or formula (XIb), where m is 9. In some embodiments, the substituent is formula (XIa) or formula (XIb), where m is 11.

In some embodiments, the substituent provides one or more 8-amino-3,6-dioxaoctanoic acids (OEGs), such as two OEGs.

In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy }ethoxy)acetyl].

In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl] cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments, the GLP-1 agonist is semaglutide, also known as N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17 -carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37) (SEQ ID NO. 4), which can be prepared as described in WO2006/097537, example 4, with the following structure:

.

In one embodiment, the GLP-1 agonist is a GLP-1 agonist B that is diacylated [Aib8,Arg34,Lys37]GLP-1(7-37) (SEQ ID NO. 5) shown in Example 2 of WO2011/080103 and called N ^ε26 {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy ]acetylamino}ethoxy)ethoxy]acetyl}, N ^ε37 -{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy) decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}[Aib ⁸ ,Arg ³⁴ ,Lys ³⁷ ]GLP-1(7-37)-peptide with the following structure: .

In one embodiment, the GLP-1 agonist is a GLP-1 C agonist that is diacylated [Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]GLP-1(7-37)-peptidyl-Glu-Gly (SEQ ID NO. 6) shown in Example 31 of WO2012/140117 and named N ^ε27 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4 -[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl], N ^ε36 -[2-[2-[2-[[2-[2- [2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl][Aib8,Glu22,Arg26 ,Lys27, Glu30,Arg34,Lys36]GLP-1(7-37)-peptidyl-Glu-Gly with the following structure:

.

In general, the term GLP-1 agonist is intended to include a GLP-1 agonist and any pharmaceutically acceptable salt, amide, or ester thereof. In some embodiments, the composition contains a GLP-1 agonist or a pharmaceutically acceptable salt, amide, or ester thereof. In some embodiments, the composition contains a GLP-1 agonist and one or more pharmaceutically acceptable counterions.

In some embodiments, the GLP-1 agonist is selected from one or more of the GLP-1 agonists set forth in WO93/19175, WO96/29342, WO98/08871, WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/ 027978, WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810, WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050, WO 2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments, the GLP-1 agonist is selected from the group consisting of

N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxinonedecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy}acetylamino)ethoxy]ethoxy}acetyl[deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxinonedecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy}acetylamino)ethoxy]ethoxy}acetyl[deamino-His7,Arg34]GLP-1(7-37);

N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino) ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]-3-carboxypropionylamino)ethoxy) ethoxy]acetylamino)ethoxy]ethoxy)acetyl][deamino-His7,Glu22,Arg26,Arg 34,Phe(m-CF3)28]GLP-1(7-37)-amide;

N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1(7-37);

N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1(7 -37);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy) acetyl][Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino ]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8,Lys26]GLP-1(7-37)-amide;

N-epsilon26-[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy )ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Lys26]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desamino-His7,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-34);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-34);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-34);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-35);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-35);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-36)-amide;

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-35);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1(7-34);

N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-36)-amide;

N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[ 2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl) butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34 ]GLP-1(7-36)-amide;

N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino )ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy ]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy )ethoxy]acetylamino)ethoxy]ethoxy)acetyl][deamino-His7, Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deamino-His7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole-5 -yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-(3-((2-(2-(2-(2-(2-hexadecyloxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy))propionyl)[desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP -1(7-37)-amide; N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}[deamino-His7 ,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)} [deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy) acetyl)[deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl][desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetyl][desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino )butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-butyl-2H-tetrazol-5-yl )hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[deamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1(7-37)-peptide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetyl][desamino-His7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetyl][deamino-His7,Glu22,Arg26,Glu30,Arg34,Lys36]GLP-1(7-37)-Glu-Lys-peptide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxinonedecanoylamino)methyl]cyclohexanecarbonyl}amino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetyl][Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1(7-37);

N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37]GLP-1(7-37);

N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [ImPr7,Glu22,Arg26,34,Lys37]GLP-1(7-37);

N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino }ethoxy)ethoxy]acetyl};

N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino }ethoxy)ethoxy]acetyl}[Aib8,Arg34,Lys37]GLP-1(7-37)-OH;

N-epsilon26-(17-carboxyheptadecanoyl)[Aib8,Arg34]GLP-1(7-37)-peptide;

N-epsilon26-(19-carboxinonedecanoyl)[Aib8,Arg34]GLP-1(7-37);

N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypentadecanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [3-(4-imidazolyl)propionyl7,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)(carboxymethylamino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Gly8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg34]GLP-1(7-37)-amide;

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg34,Pro37]GLP-1(7-37)-amide, Aib8,Lys26-(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino )-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)})-Arg34)GLP-1-H(7-37)-OH;

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino] ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);

N-alpha-7-formyl, N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy] acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Glu22,Arg34]GLP-1(7-37);

N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dicarboxypropyl )carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino] (4(S)-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);

N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19 -carboxynonadecanoylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1(7-37);

N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl[Aib8,Arg34]GLP-1(7-37);

N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy ]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1(7-37);

N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}[Aib8 ,22,27,30,35,Arg34,Pro37,Lys26]GLP-1(7-37)-amide;

N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37) and

N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8,Arg34]GLP-1(7-37).

Delivery vehicle

N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt

The delivery vehicle used in the present invention is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC). The structural formula of N-(8-(2-hydroxybenzoyl)amino)caprylate is shown as Formula (I).

(I).

In some embodiments, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt contains one monovalent cation, two monovalent cations, or one divalent cation. In some embodiments, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is selected from the group consisting of the sodium salt, potassium salt, and/or calcium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In one embodiment, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is selected from the group consisting of sodium salt, potassium salt and/or ammonium salt. In one embodiment, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is a sodium salt or a potassium salt. N-(8-(2-hydroxybenzoyl)amino)caprylate salts can be prepared using the method described, for example, in WO96/030036, WO00/046182, WO01/092206 or WO2008/028859.

The N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt may be crystalline and/or amorphous. In some embodiments, the delivery vehicle comprises one-third N-(8-(2-hydroxybenzoyl)amino)caprylic acid anhydrate, monohydrate, dihydrate, trihydrate, solvate, or hydrate, as well as combinations thereof. In some embodiments, the delivery vehicle is the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt described in WO2007/121318.

In some embodiments, the delivery vehicle is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to herein as “SNAC”), also known as sodium 8-(salicylamino)octanoate.

Composition

The composition or pharmaceutical composition of the present invention is a solid or dry composition suitable for administration via the oral route, as further described herein below.

In some embodiments, the composition contains at least one pharmaceutically acceptable excipient. As used herein, the term "excipient" broadly refers to any component other than the active therapeutic ingredient(s) or active pharmaceutical ingredient(s). (API). The excipient may be a pharmaceutically inert substance, an inactive substance, and/or a therapeutically or medically inactive substance.

Excipients can serve various purposes, for example, as a carrier, carrier medium, filler, binder, lubricant, glidant, disintegrant, flow control agent, crystallization inhibitors, solubilizer, stabilizer, coloring agent, flavoring agent, surfactant. active substance, emulsifier or combinations thereof, and/or to improve the administration and/or absorption of therapeutically active substance(s) or active pharmaceutical ingredient(s). The amount of each excipient used may vary within ranges conventional in the art. Techniques and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 8th edition, Sheskey et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017); and Remington: the Science and Practice of Pharmacy, 22nd edition, Remington and Allen, Eds., Pharmaceutical Press (2013).

In some embodiments, the excipients may be selected from binders such as polyvinylpyrrolidone (povidone), etc.; fillers such as cellulose powder, microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, etc.; lubricants and/or glidants such as stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate, etc.; flow control agents such as fumed silica, talc, etc.; crystallization inhibitors such as povidone, etc.; solubilizers such as Pluronic, povidone, etc.; coloring agents including dyes and pigments such as iron oxide red or yellow, titanium dioxide, talc, etc.; pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, etc.; surfactants and emulsifiers such as Pluronic, polyethylene glycols, sodium carboxymethylcellulose, polyethoxylated and hydrogenated castor oil, etc.; and mixtures of two or more such excipients and/or adjuvants.

The composition may contain a binder such as povidone; varieties of starch; cellulose varieties and their derivatives, such as microcrystalline cellulose, for example, Avicel PH from FMC (Philadelphia, PA), hydroxypropylcellulose, hydroxyethylcellulose and METHOCEL hydroxylpropylmethylcellulose from Dow Chemical Corp. (Midland, Michigan); sucrose; dextrose; corn syrup; polysaccharides and gelatin. The binder may be selected from the group consisting of dry binders and/or wet granulation binders. Suitable dry binders are, for example, cellulose powder and microcrystalline cellulose, such as Avicel PH 102 and Avicel PH 200. In some embodiments, the composition contains Avicel, such as Avicel PH 102. Suitable binders for wet granulation or dry granulation are corn starch , polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (copovidone) and cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxylpropylmethylcellulose. In some embodiments, the composition contains povidone.

In some embodiments, the composition contains a filler that may be selected from lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate such as calcium hydrogen phosphate, microcrystalline cellulose, powdered cellulose, confectioner's sugar, compressed sugar, dextrate, dextrin and dextrose. In some embodiments, the composition contains microcrystalline cellulose, such as Avicel PH 102 or Avicel PH 200.

In some embodiments, the composition contains a lubricant and/or a glidant. In some embodiments, the composition contains a lubricant and/or glidant such as talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, glyceryl dibehenate, behenoylpolyoxyl-8-glycerides, polyethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate , sodium stearyl fumarate, stearic acid, hydrogenated vegetable oils, silicon dioxide and/or polyethylene glycol, etc. In some embodiments, the composition contains magnesium stearate or glyceryl dibehenate (such as Compritol® 888 ATO, which consists of mono-, di-, and triesters of behenic acid (C22), with a predominant diester fraction).

In some embodiments, the composition contains a disintegrant such as sodium starch glycolate, potassium polacrilin, sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, or dried corn starch.

The composition may contain one or more surfactants, for example, a surfactant, at least one surfactant, or two different surfactants. The term "surfactant" refers to any molecules or ions that contain a water-soluble (hydrophilic) portion and a fat-soluble (lipophilic) portion. For example, the surfactant may be selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants and/or zwitterionic surfactants.

As shown in the examples herein, the compositions of the present invention are characterized by a very high content of delivery vehicle. Such very high content may be defined relative to the total tablet content also including the active pharmaceutical ingredient (ie, GLP-1 agonist) or, alternatively, relative to the total excipient content excluding the active pharmaceutical ingredient. The description below also applies to compositions consisting of the specific ingredients, GLP-1 agonist and excipients, the term “consisting of” being understood to still include trace amounts of any substance not having an effect on the function of the composition, which may also be designated as “consisting essentially of.” Such substances may be impurities remaining during the preparation of the GLP-1 agonist or the preparation of the NAC salt, or minimal amounts (less than 1%) of any pharmaceutically acceptable excipient that does not affect the quality or absorption of the formulation.

In one embodiment, the pharmaceutical composition contains:

a. GLP-1 agonist and

b. N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt (NAC),

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 90% w/w of the composition or more.

In such further embodiments, the NAC salt is greater than 91%, such as greater than 92%, such as greater than 93, such as greater than 94%, such as greater than 95% w/w of the composition.

In such further embodiments, the NAC salt is at least 91% w/w, such as at least 92% w/w, such as at least 93% w/w, such as at least 94% w/w, such as at least 95% w/w of said composition.

In one embodiment, the pharmaceutical composition contains:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt (NAC),

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 90% w/w of the excipients of the composition.

In one embodiment, the pharmaceutical composition consists of:

a) a GLP-1 agonist and

b) excipients, where the excipients are:

i. salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) and

ii. one or more additional excipients;

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 90% w/w of the excipients of the composition.

In such further embodiments, the NAC salt is at least 91% w/w, such as at least 92% w/w, such as at least 93% w/w, such as at least 94% w/w /weight, such as at least 95% w/w of the excipients of the composition.

In one embodiment, the pharmaceutical composition contains:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt (NAC),

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 95% w/w of the excipients of the composition.

In one embodiment, the pharmaceutical composition consists of:

a) a GLP-1 agonist and

b) excipients, where the excipients are:

i. salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) and

ii. one or more additional excipients;

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 95% w/w of the excipients of the composition.

In such further embodiments, the NAC salt is greater than 95% w/w, such as greater than 96% w/w, such as greater than 97% w/w, or such as greater than 98% w/w of the composition.

In such further embodiments, the NAC salt is at least 95% w/w, such as at least 96% w/w, such as at least 97% w/w, or such as at least 98% w/w of excipients of the composition.

As stated above, according to the present invention, the content of excipients other than the delivery agent is preferably minimal. In one embodiment, the pharmaceutical composition contains at least one lubricant.

In one embodiment, the pharmaceutical composition contains or consists of:

a) GLP-1 agonist,

b) salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) and

c) at least one lubricant.

In such embodiments, the lubricant may be magnesium stearate or glyceryl dibehenate. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is glyceryl dibehenate.

The composition described above, wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 95% w/w of the excipients of the composition, may further be a composition wherein said salt constitutes at least at least 90% w/w of the composition or more.

Similar to the compositions described above, wherein said salt constitutes at least 90% w/w or more, the composition may further be a composition wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 95% w/w of the excipients of the composition.

The pharmaceutical composition may further be a composition wherein the N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt is selected from the group consisting of sodium salt, potassium salt and/or calcium salt N-(8-(2 -hydroxybenzoyl)amino)caprylic acid (NAC) or, alternatively, from the group consisting only of sodium salt and potassium salt. In one embodiment, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.

In embodiments where said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 90% w/w of the excipients of the composition, the composition contains no more than 10% w/w of any additional excipients , such as a binder, filler and/or lubricant/glidant. In some embodiments, the composition contains at least 90% w/w or more delivery vehicle and less than 5% w/w any additional excipients such as a binder, filler, and/or lubricant/glidant. In one embodiment, the pharmaceutical composition contains at least 90% w/w delivery vehicle and less than 5% w/w lubricant. In one embodiment, the pharmaceutical composition contains at least 90% w/w delivery vehicle and less than 3% w/w lubricant.

In some embodiments, the composition contains at least 90% w/w or more delivery vehicle and 0.1-5% w/w, such as 0.5-4% w/w or 1-3% w/w , lubricant. In such additional embodiments, the composition contains 2-2.5% w/w lubricant.

In embodiments where said N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt constitutes at least 95% w/w of the excipients of the composition, the composition contains no more than 5% w/w of any additional excipients , such as a binder, filler and/or lubricant/glidant. In some embodiments, the composition contains at least 95% w/w delivery vehicle and less than 5% w/w lubricant. In one embodiment, the pharmaceutical composition contains at least 95% w/w delivery vehicle and less than 3% w/w lubricant.

In some embodiments, the composition contains at least 95% w/w delivery vehicle and 0.1-5% w/w, such as 0.5-4% w/w or 1-3% w/w lubricant substances. In such additional embodiments, the composition contains 2-2.5% w/w lubricant.

The pharmaceutical composition in accordance with the present invention is preferably prepared in a dosage form suitable for oral administration, as described herein below. The following are absolute quantities of the ingredients of the composition of the present invention with reference to the content per dosage unit, i.e. per tablet, capsule or sachet.

In a further embodiment, the pharmaceutical compositions of the present invention may contain no more than 1000 mg of said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt per dosage unit. In one embodiment, the present invention provides a composition wherein a dosage unit contains no more than 500 mg of said salt.

In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt per dosage unit is at least 0.05 mmol, such as at least 0.075 mmol, such as at least 0 ,1 mmol, such as at least 0.125 mmol, such as at least 0.15 mmol, such as at least 0.20 mmol, at least 0.25 mmol, at least 0 .30 mmol, at least 0.35 mmol, at least 0.40 mmol, at least 0.45 mmol, at least 0.50 mmol, at least 0.55 mmol or at least 0.60 mmol.

In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt per dosage unit of the composition is no more than 3 mmol, such as no more than 2.75 mmol, such as no more than 2.5 mmol, such as, for example, not more than 2.25 mmol, such as, for example, 2 mmol, such as, for example, not more than 1.5 mmol, not more than 1 mmol, not more than 0.75 mmol, not more than 0.6 mmol, no more than 0.5 mmol, no more than 0.4 mmol, no more than 0.3 mmol and no more than 0.2 mmol.

In some embodiments, the amount of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt per unit dose of the composition is in the range of 0.05-3 mmol, 0.10-2.5 mmol, 0.15-2.0 mmol, 0.20-1.5 mmol, 0.25-1.0 mmol, 0.30-0.75 mmol or such as 0.45-0.65 mmol.

In some embodiments, where the NAC salt is SNAC, the amount of SNAC in the composition is at least 20 mg, such as at least 25 mg, such as at least 50 mg, such as at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg and at least 300 mg per dose unit.

In some embodiments, where the NAC salt is SNAC, the amount of SNAC in the composition is no more than 800 mg, such as no more than 600 mg, such as no more than 575 mg, such as no more than 550 mg, no more than 525 mg, no more than 500 mg, no more than 475 mg, no more than 450 mg, no more than 425 mg, no more than 400 mg, no more than 375 mg, no more than 350 mg, no more than 325 mg per dose unit or no more than 300 mg per dose unit.

In some embodiments, where the NAC salt is SNAC, the amount of SNAC in the composition is in the range of 20-800 mg, such as 25-600 mg, such as 50-500 mg, such as 50-400 mg , such as 75-400 mg, such as 80-350 mg, or such as about 100 to about 300 mg per dosage unit.

In one embodiment, where the NAC salt is SNAC, the amount of SNAC is in the range of 20-200 mg, such as 25-175 mg, such as 75-150 mg, such as 80-120 mg, such as eg approximately 100 mg per dose unit.

In one embodiment, where the NAC salt is SNAC, the amount of SNAC is in the range of 200-800 mg, such as 250-400 mg, such as 250-350 mg, such as 275-325 mg, such as eg approximately 300 mg per dose unit.

In one embodiment, a dosage unit of the pharmaceutical compositions of the present invention contains 0.1 to 100 mg or 0.2 to 100 mg of a GLP-1 agonist.

In some embodiments, a dosage unit of the composition contains an amount of GLP-1 agonist that ranges from 0.2 to 50 mg or from 1 to 40 mg.

In some embodiments, a dosage unit contains 0.5-5 mg of GLP-1 agonist, such as 0.75-4.5 mg, such as 1, 1.5, 2, 2.5 or 3 mg, or 3.5, 4, 4.5 mg, such as 1-3 or 3-5 mg GLP-1 agonist per dose unit.

In some embodiments, a dosage unit contains from 2 to 20 mg of GLP-1 agonist, such as 2-15 mg, such as 2, 3, 4, 5, 6, or 7 mg, such as 2, 3 , 4 or 5 mg or such as 8, 10, 12 or 14 mg, such as 15 mg or such as 20 mg GLP-1 agonist per dose unit.

In some embodiments, a dosage unit contains from 5 to 50 mg of GLP-1 agonist, such as 10-45 mg, such as 20, 30 or 40 mg, or such as 25, 35 or 45 mg, or such as 30-50 mg, or such as 20-40 mg GLP-1 agonist per dose unit.

The amount of GLP-1 agonist may vary depending on the nature of the GLP-1 agonist and the desired effect, i.e. higher levels may be appropriate in the treatment of obesity as opposed to the treatment of diabetes.

In a preferred embodiment, a single dose of the composition contains 0.5-25 mg magnesium stearate, such as 1-10 mg, such as 2-8 mg, or such as 2-5 mg magnesium stearate.

In a preferred embodiment, the amount of magnesium stearate is determined relative to the amount of NAC salt, such as SNAC, such that a single dose of the composition contains 1-8 mg magnesium stearate, or such as 2-5 mg magnesium stearate, or 2-3 mg magnesium stearate per 100 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt, e.g. SNAC.

In a preferred embodiment, a single dose of the composition contains 80-120 mg SNAC, 0.5-5 mg GLP-1 agonist and 2-3 mg lubricant.

In a preferred embodiment, a single dose of the composition contains 80-120 mg SNAC, 1.5-10 mg GLP-1 agonist and 2-3 mg lubricant.

In a preferred embodiment, a single dose of the composition contains 80-120 mg SNAC, 5-50 mg GLP-1 agonist and 2-3 mg lubricant.

In a preferred embodiment, a single dose of the composition contains 250-350 mg SNAC, 0.5-5 mg GLP-1 agonist and 3-10 mg lubricant.

In a preferred embodiment, a single dose of the composition contains 250-350 mg SNAC, 1.5-10 mg GLP-1 agonist and 3-10 mg lubricant.

In a preferred embodiment, a single dose of the composition contains 250-350 mg SNAC, 5-50 mg GLP-1 agonist and 3-10 mg lubricant.

In one embodiment, the pharmaceutical composition of the present invention is characterized by rapid release in vitro. Release or dissolution can be tested as known in the art and as described herein in Assay I. Release can be expressed as the amount of GLP-1 agonist measured in solution after a specified period, relative to the total GLP-1 agonist content of the composition. The relative amount may be expressed as a percentage. In one embodiment, the release of the GLP-1 agonist from the pharmaceutical composition of the present invention is at least 85% within 15 minutes or at least 95% within 30 minutes. In one such embodiment, release is measured at pH 6.8.

In one embodiment, the pharmaceutical composition contains:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

where the release of the GLP-1 agonist reaches 85% within 15 minutes or 95% within 30 minutes. In one embodiment, release is measured at pH 6.8.

In one embodiment, the pharmaceutical composition of the present invention provides early exposure in vivo. In one embodiment, the pharmaceutical composition of the present invention provides increased in vivo exposure. In one embodiment, the pharmaceutical composition of the present invention provides increased early in vivo exposure. Such in vivo exposure can be tested in an appropriate model, such as Assay III described herein. As shown in Table 3.1, the compositions disclosed herein demonstrate increased early dose-adjusted exposure in Beagle dogs within the first 30 minutes after oral dosing. Exposure can also be measured over a predetermined period of time and a cumulative dose-adjusted exposure (AUC) calculated, for example over t=0-30 minutes, also presented in Table 3.1 for the compositions described herein.

In one embodiment, the present invention relates to a pharmaceutical composition, wherein the dose-adjusted exposure at t=30 min. is an improvement over the composition described in WO2013/139694, which contains additional excipients, microcrystalline cellulose and povidone. The reference composition for said GLP-1 agonist should preferably be prepared using two beads disclosed as type F and H in WO2013/139694 and prepared by replacing semaglutide/compound A with the GLP-1 agonist of interest.

In one embodiment, the pharmaceutical composition contains:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

where dose-adjusted exposure at t=30 min. is increased relative to the composition type F/H from WO2013/139694.

In one embodiment, the pharmaceutical composition contains:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

where dose-adjusted exposure (AUC) during t=0-30 min. is increased relative to the composition type F/H from WO2013/139694.

In one embodiment, the dose-adjusted exposure (AUC) during t=0-30 minutes. is increased by at least 1.5 times, for example 2 times, compared to the composition type F/H from WO2013/139694.

Dosage form

The composition can be administered in several dosage forms, for example, as a tablet; coated tablet; a sachet or capsule, such as hard or soft gelatin capsules.

The composition may further be formulated with a drug carrier or drug delivery system, for example, to increase stability and/or solubility or to further increase bioavailability. The composition may be a lyophilized or spray-dried composition.

The composition may be in the form of a dosage unit, such as a tablet. In some embodiments, the single dose weight is in the range of 50 mg to 1000 mg, such as in the range of 50-750 mg or such as in the range of 100-500 mg.

In some embodiments, the dosage unit weight is in the range of 75 mg to 350 mg, such as in the range of 100-300 mg or such as in the range of 200-350 mg.

In some embodiments, the dosage unit weight is in the range of 100 mg to 400 mg, such as in the range of 50-300 mg or such as in the range of 200-400 mg.

In some embodiments, the composition may be granulated prior to compaction. The composition may contain an intragranular portion and/or an extragranular portion, wherein the intragranular portion has been tucked under granulation and the extragranular portion has been added after granulation.

The intragranular portion may contain a GLP-1 agonist, a delivery vehicle, and/or an excipient such as a lubricant and/or a glidant. In some embodiments, the intragranular portion comprises a delivery vehicle and a lubricant and/or glidant.

The extragranular portion may contain a GLP-1 agonist and/or a lubricant and/or a glidant such as magnesium stearate. In some embodiments, the extragranular portion comprises a GLP-1 agonist. In some embodiments, the extragranular portion comprises an excipient such as a lubricant and/or a glidant such as magnesium stearate.

In additional embodiments, the intragranular portion comprises a GLP-1 agonist, a delivery vehicle, and a lubricant and/or glidant. In such embodiments, the granulate can be directly compressed into tablets, and the tablets do not have an extragranular portion.

Receiving a composition

The preparation of the composition in accordance with the present invention can be carried out in accordance with methods known in the art.

To obtain a dry mixture of tableting material, the various components are weighed, optionally rubbed or sifted, and then combined. Mixing the components can be carried out until a homogeneous mixture is obtained.

If granules are to be used in the tabletting material, the granules can be produced in a manner known to one skilled in the art, for example using wet granulation methods known to produce "agglomerated" granules or "grind" granules. Methods for forming agglomerated granules can be carried out continuously and involve, for example, simultaneous spraying of the granulation mass with the granulation solution and drying, for example in a drum granulator, in disc granulators, in disk granulators, in a fluidized bed, by spray drying, spray granulation or curing method spray drying, or performed intermittently, for example, in a fluidized bed, in a rotary fluidized bed, in a batch mixer such as a high shear mixer or a low shear mixer, or in a spray drying drum. Processes for producing grindable granules, which may be carried out intermittently, in which the granulation mass first forms a wet aggregate with the granulation solution, which is further crushed or otherwise formed into granules of the required size, and then the granules can be dried. Suitable equipment for the wet granulation step are planetary mixers, low shear mixers, high shear mixers, extruders and spheronizers such as those from Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach, Alexanderwerk, Ytron, Wyss & Probst , Werner & Pfleiderer, HKD, Loser, Fuji, Nica, Caleva and Gabler. Granules can also be formed by dry granulation techniques, in which one or more excipients and/or an active pharmaceutical ingredient are compressed to form relatively large compacted formations, such as bars or strips, which are reduced by crushing, and the crushed material serves as tabletting material, subject to further compaction. Suitable equipment for dry granulation without limitation is the roller mill from Gerteis, such as the Gerteis MICRO-PACTOR, MINI-PACTOR and MACRO-PACTOR.

The terms "granulate" and "granules" are used interchangeably herein to refer to particles of the composite material that can be prepared as described above.

A tablet press may be used to compact the tableting material into a solid oral dosage form, such as a tablet. In a tablet press, the tableting material is filled (for example, by force feed or gravity feed) into a die cavity. The tableting material is then compacted using a set of punches while applying pressure. Subsequently, the resulting compressed product or tablet is removed from the tablet press. The above-mentioned tabletting method is hereinafter referred to as "compaction method". Suitable tablet presses include, but are not limited to, rotary tablet presses and eccentric tablet presses. Examples of tablet presses include, but are not limited to, the Fette 102i (Fette GmbH), the Korsch XL100, the Korsch PH 106 rotary tablet press (Korsch AG, Germany), the Korsch EK-O eccentric tablet press (Korsch AG, Germany), and the Manesty F-Press (Manesty Machines Ltd., UK).

In one embodiment, the composition contains at least one granule. In one embodiment, the composition contains one type of granule. Alternatively, the composition may contain two types of granules.

In some embodiments, the method of producing a tablet involves: a) granulating a mixture containing a delivery vehicle and optionally a lubricant; b) mixing the granulate from a) with the GLP-1 agonist and optionally an additional lubricant, and then c) compressing the mixture from b) into tablets.

In some embodiments, a method of preparing a tablet comprises: a) granulating a mixture containing a delivery vehicle, a GLP-1 agonist, and optionally a lubricant, and b) compressing the granulate from a) into tablets and optionally including an additional lubricant.

In general, granulates can be produced by wet granulation, melt granulation or dry granulation, preferably dry granulation.

Indications for use of the pharmaceutical drug

The present invention also relates to the composition of the present invention for use as a medicinal product. In specific embodiments, the composition of the present invention can be used in the following therapeutic treatments, preferably all of them in some way related to diabetes and/or obesity:

(i) prevention and/or treatment of all forms of diabetes mellitus, such as hyperglycemia, type 2 diabetes mellitus, impaired glucose tolerance, type 1 diabetes mellitus, non-insulin-dependent diabetes mellitus, MODY (maturity-onset diabetes mellitus of the young), gestational diabetes mellitus and /or decrease in HbA1C level;

(ii) delaying or preventing the progression of a diabetic disease, such as the progression of type 2 diabetes mellitus, delaying the progression of impaired glucose tolerance (IGT) to insulin-dependent type 2 diabetes mellitus and/or delaying the progression of non-insulin-dependent type 2 diabetes mellitus to insulin-dependent type 2 diabetes mellitus;

(iii) improving β-cell function, eg, reducing β-cell apoptosis, increasing β-cell function and/or β-cell mass, and/or restoring β-cell glucose sensitivity;

(iv) prevention and/or treatment of cognitive impairment;

(v) preventing and/or treating eating disorders such as obesity, for example, by reducing food intake, reducing body weight, suppressing appetite, inducing a feeling of satiety; treatment or prevention of binge eating disorder, bulimia nervosa and/or obesity caused by the administration of an antipsychotic drug or steroid; decreased gastric motility and/or delayed gastric emptying.

(vi) prevention and/or treatment of complications of diabetes, such as neuropathy, including peripheral neuropathy; nephropathy or retinopathy;

(vii) improving lipid metabolism, for example, preventing and/or treating dyslipidemia, reducing total lipids in the blood serum; reduction of HDL content; reduction in the content of small dense LDL; reduction of VLDL content; reduction of triglycerides; lowering cholesterol levels; increased HDL, decreased levels of lipoprotein a (Lp(a)) in human plasma; inhibition of apoliprotein a (apo(A)) formation in vitro and/or in vivo;

(iix) prevention and/or treatment of cardiovascular diseases such as syndrome X; atherosclerosis; myocardial infarction; coronary heart disease; stroke, cerebral ischemia; early stage heart disease or early stage cardiovascular disease, such as left ventricular hypertrophy; cardiac ischemia; essential hypertension; acute hypertensive crisis; cardiomyopathy; heart failure; exercise tolerance; chronic heart failure; arrhythmia; heart rhythm disturbance; fainting; atherosclerosis; moderate chronic heart failure; angina pectoris; stent reocclusion after bypass surgery; dynamic circulatory disorder (atheroschlerosis obliterens); diastolic dysfunction and/or systolic dysfunction;

(ix) prevention and/or treatment of gastrointestinal diseases such as inflammatory bowel syndrome; short bowel syndrome or Crohn's disease; dyspepsia and/or stomach ulcers;

(x) prevention and/or treatment of critical illness, for example, treatment of a critically ill patient, a patient with critical illness polyneuropathy (CIPNP) and/or a patient with potential CIPNP; preventing the development of critical illness or CIPNP; preventing, treating and/or curing systemic inflammatory response syndrome (SIRS) in a patient and/or to prevent or reduce the likelihood of a patient developing bacteremia, septicemia and/or septic shock during hospitalization; and/or

(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS).

In a specific embodiment, the indication is selected from the group consisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii) and/or (iii); or indications (v), indications (vi), indications (vii) and/or indications (iix). In another specific embodiment, the indication is (i). In a further specific embodiment, the indication is (v). In yet another specific embodiment, the indication is (iix). In some embodiments, the indication is type 2 diabetes and/or obesity.

Method of treatment

The present invention further provides a method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition in accordance with the present invention. In one embodiment, the treatment method is for the treatment of diabetes mellitus or obesity and/or additional indications identified above.

In some embodiments, a method of treating diabetes mellitus is described comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a GLP-1 agonist, an N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) salt, and optionally lubricant.

In some embodiments, a method of treating diabetes mellitus is described comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 0.5-50 mg of a GLP-1 agonist, 50-500 mg of N-(8-(2-hydroxybenzoyl) salt )amino)caprylic acid (NAC) and 1-10 mg lubricant. In a preferred embodiment, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% (w/w) of the composition.

In a preferred embodiment, the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 95% (w/w) of the excipients of the composition.

In an alternative embodiment, a method of treating diabetes mellitus is described comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising about 1-14 mg of a GLP-1 agonist, about 100-300 mg of N-(8-(2-hydroxybenzoyl) salt )amino)caprylic acid (NAC) and approximately 2-8 mg magnesium stearate.

In some embodiments, the GLP-1 agonist is semaglutide with the formula N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino )butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37), and N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt (NAC) is sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC). Various examples of lubricant are described, including magnesium stearate. The composition is administered orally and is in the form of a tablet, capsule or sachet.

In such further embodiments, one or more dosage units may be administered to a specified subject in need thereof.

Combined treatment

Treatment with the composition according to the present invention can also be combined with one or more additional active pharmaceutical ingredients, for example selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications arising as a result of or associated with diabetes mellitus, and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. Examples of these biologically active substances are: insulin, sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors; canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin, remogliflozin etabonate and sotagliflozin, in particular dapagliflozin and empagliflozin, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, absorption modulators glucose, compounds that modify lipid metabolism , such as antihyperlipidemic agents such as HMG CoA inhibitors (statins), gastric inhibitory polypeptides (GIP analogues), compounds that reduce food absorption, RXR agonists and agents acting on the ATP-dependent potassium channel of β-cells; cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, dextrothyroxine, neteglinide, repaglinide; β-blockers such as alprenolol, atenolol, timolol, rindolol, propranolol and metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, alatriopril, quinapril and ramipril, calcium channel blockers such as nifedipine , felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin; CART (cocaine-amphetamine-regulated transcript) agonists, NPY (neuropeptide Y) antagonists, PYY agonists, Y2 receptor agonists, Y4 receptor agonists, mixed Y2/Y4 receptor agonists, MC4 (melanocortin 4) agonists, orexin antagonists, agonists TNF (tumor necrosis factor), CRF (corticotropin-releasing factor) agonists, CRF BP (corticotropin-releasing factor binding protein) antagonists, urocortin agonists, β3-agonists, oxyntomodulin and analogs, MSH (melanocyte-stimulating hormone) agonists, antagonists MCH (melanocyte-concentrating hormone), CCK (cholecystokinin) agonists, serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, releasing hormone growth hormone compounds, TRH (thyrotropin-releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor) modulators, TR β agonists; histamine H3 receptor antagonists, gastric inhibitory polypeptide agonists or antagonists (GIP analogs), gastrin and gastrin analogs.

The present invention described herein is, without limitation, further defined by the embodiments described below and the claims herein.

Embodiments

1. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w of the composition.

2. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition.

3. Pharmaceutical composition consisting of:

a) a GLP-1 agonist and

b) excipients, where the excipients are:

i. salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and

ii. one or more additional excipients;

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition.

4. The pharmaceutical composition according to any of the previous embodiments 1 to 3, wherein the composition contains at least one lubricant.

5. Pharmaceutical composition consisting of:

a) GLP-1 agonist,

b) salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and

c) at least one lubricant.

6. The pharmaceutical composition according to any of the previous embodiments 4 and 5, wherein the lubricant is magnesium stearate.

7. The pharmaceutical composition according to any of the previous embodiments, wherein the composition contains 1-8 mg, such as 2-5 mg or such as 2-3 mg, magnesium stearate per 100 mg of N-(8- (2-hydroxybenzoyl)amino)caprylic acid.

8. The pharmaceutical composition according to any of the preceding embodiments 2-7, wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w of the composition.

9. The pharmaceutical composition according to any of the preceding embodiments 1, 5-8, wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 95% w/w of the excipients of the composition.

10. The pharmaceutical composition according to any of the previous embodiments, wherein the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is selected from the group consisting of sodium salt, potassium salt and/or calcium salt N-(8- (2-hydroxybenzoyl)amino)caprylic acid.

11. The pharmaceutical composition according to any of the preceding embodiments, wherein the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).

12. The pharmaceutical composition according to any of the previous embodiments, wherein the dose unit contains not more than 1000 mg of said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt.

13. The pharmaceutical composition according to any of the previous embodiments, wherein the dose unit contains 0.5-50 mg of a GLP-1 agonist.

14. The pharmaceutical composition according to any of the preceding embodiments, wherein the GLP-1 agonist has a T½ in minipigs of at least 24 hours.

15. The pharmaceutical composition according to any of the preceding embodiments, wherein the GLP-1 agonist has an EC50 (non-HSA assay) of no more than 100 pM, such as no more than 50.

16. The pharmaceutical composition according to any of the preceding embodiments, wherein the GLP-1 agonist is selected from the group consisting of liraglutide, semaglutide, a GLP-1 B agonist, and a GLP-1 C agonist.

17. The pharmaceutical composition according to any of the preceding embodiments, wherein the GLP-1 agonist is selected from the group consisting of semaglutide and a GLP-1 agonist C.

18. The pharmaceutical composition according to any of the previous embodiments, wherein the composition contains at least one granule.

19. The pharmaceutical composition according to the previous embodiment 18, wherein at least one granule contains a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

20. The pharmaceutical composition according to any of the previous embodiments 18-19, wherein the at least one granule further contains a lubricant such as magnesium stearate.

21. The pharmaceutical composition according to any of the previous embodiments 18-20, wherein the at least one granule further contains a GLP-1 agonist.

22. The pharmaceutical composition according to any of the previous embodiments 18-21, wherein the at least one granulate is produced by dry granulation, such as by rolling.

23. The pharmaceutical composition according to any of the preceding embodiments 18-22, wherein the composition contains an extragranular portion.

24. The pharmaceutical composition according to any of the preceding embodiments 18-23, wherein the extragranular portion of the composition contains a lubricant or glidant such as magnesium stearate, and/or a GLP-1 agonist.

25. Pharmaceutical composition containing:

a) 0.5-50 mg GLP-1 agonist and

b) 20-800 mg, such as 25-600, such as 50-500 mg, N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

26. Pharmaceutical composition containing:

a) 1-25 mg GLP-1 agonist and

b) 50-400 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

27. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 75-150 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

28. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 75-125 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

29. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 80-120 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

30. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 200-400 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

31. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 250-350 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is semaglutide.

32. Pharmaceutical composition containing:

a) 0.1-25 mg GLP-1 agonist and

b) 20-800 mg, such as 25-600, 50-500 mg, N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is a GLP-1 C agonist.

33. Pharmaceutical composition containing:

a) 1-25 mg GLP-1 agonist and

b) 50-400 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is a GLP-1 C agonist.

34. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 75-150 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is a GLP-1 C agonist.

35. Pharmaceutical composition containing:

c) 1-15 mg GLP-1 agonist and

d) 75-125 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is a GLP-1 C agonist.

36. Pharmaceutical composition containing:

c) 1-15 mg GLP-1 agonist and

d) 80-120 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is a GLP-1 C agonist.

37. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 200-400 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 90% w/w, such as at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is is a GLP-1 C agonist.

38. Pharmaceutical composition containing:

a) 1-15 mg GLP-1 agonist and

b) 250-350 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 95% w/w of the excipients of the composition, and wherein the GLP-1 agonist is a GLP-1 C agonist.

39. The pharmaceutical composition according to any of embodiments 25-38, further comprising 1-10 mg of a lubricant such as magnesium stearate.

40. The pharmaceutical composition in accordance with any of embodiments 25-38, further containing 1-8 mg, such as 2-5 mg or such as 2-3 mg, magnesium stearate per 100 mg of N-(8 -(2-hydroxybenzoyl)amino)caprylic acid.

41. The pharmaceutical composition according to any of the preceding embodiments, wherein the composition is for oral administration.

42. The pharmaceutical composition according to any of the preceding embodiments, wherein the composition is a solid composition.

43. The pharmaceutical composition according to the previous embodiments, wherein the composition is a solid composition such as a tablet, capsule or sachet.

44. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

where the release of the GLP-1 agonist reaches 85% within 15 minutes or 95% within 30 minutes.

45. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

where dose-adjusted exposure at t=30 min. is increased relative to the reference composition type F/H from WO2013/139694.

46. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

where dose-adjusted exposure (AUC) during t=0-30 min. is increased relative to the reference composition type F/H from WO2013/139694.

47. The pharmaceutical composition according to the previous embodiment 46, wherein the dose-adjusted exposure (AUC) during T=0-30 minutes. is increased by at least 1.5 times, such as at least 2 times.

48. The pharmaceutical composition in accordance with any of embodiments 25-40, further defined by features from one or more of embodiments 8, 10, 11, 18-24, and 41-47.

49. The pharmaceutical composition according to embodiments 44, 45, 46, or 47, further defined by features of one or more of embodiments 4, 6-24, and 41-43.

50. A pharmaceutical composition according to any of the preceding embodiments for use in medicine.

51. A pharmaceutical composition in accordance with any of the previous embodiments for use in a method of treating diabetes mellitus and/or obesity.

52. A method of treating a subject in need thereof, wherein the method comprises administering to said subject a therapeutically active amount of a composition in accordance with any of the preceding embodiments.

Additional embodiments

1. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes at least 95% w/w of the excipients of the composition.

2. The pharmaceutical composition according to embodiment 1, further comprising at least one lubricant.

3. Pharmaceutical composition consisting of:

a) GLP-1 agonist,

b) salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and

c) at least one lubricant.

4. The pharmaceutical composition according to any of the previous embodiments, wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt constitutes more than 90% w/w of the composition.

5. The pharmaceutical composition according to any of the previous embodiments 2-4, wherein the lubricant is magnesium stearate.

6. The pharmaceutical composition according to any of the previous embodiments, wherein the dosage unit contains:

a) 0.5-50 mg GLP-1 agonist and/or

b) 50-500 mg of said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt.

7. The pharmaceutical composition according to any of the previous embodiments, wherein the dosage unit contains:

a) 0.5-50 mg GLP-1 agonist,

b) 50-500 mg of said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt and

c) 1-10 mg of a lubricant such as magnesium stearate.

8. The pharmaceutical composition according to any of the preceding embodiments, wherein the GLP-1 agonist is selected from the group consisting of liraglutide, semaglutide, a GLP-1 B agonist, and a GLP-1 C agonist.

9. The pharmaceutical composition according to any of the previous embodiments, wherein the composition is a solid composition such as an oral tablet.

10. Pharmaceutical composition containing:

a) GLP-1 agonist and

b) N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt,

Where

i. GLP-1 agonist release reaches 85% within 15 minutes, and/or

ii. dose-adjusted exposure (AUC) during t=0-30 min. is increased relative to the reference composition type F/H from WO2013/139694, and/or

iii. dose-adjusted exposure of 30 min. (AUC) is increased relative to the reference composition type F/H from WO2013/139694.

11. The pharmaceutical composition according to embodiment 10, wherein the composition has one or more features of any of embodiments 1-9.

12. A pharmaceutical composition according to any of the previous embodiments for use in medicine.

13. Pharmaceutical composition in accordance with any of the previous embodiments for use in a method of treating diabetes mellitus and/or obesity.

14. A method of treating an individual in need thereof, comprising administering to said individual a therapeutically active amount of a composition in accordance with any of the preceding embodiments.

Methods and examples

General Detection and Characterization Techniques

Analysis I: Solubility Test

The dissolution test is carried out in an appropriate solubility test device, such as the USP 2 dissolution test device, and a standard dissolution test according to the European Pharmacopoeia (Ph Eur 2.9.3) can be performed to measure the release of GLP-1 agonist and SNAC in vitro.

The data described herein is obtained using apparatus 2 in accordance with USP 35 using a stirring paddle speed of 50 rpm. To test at pH 6.8, use 500 ml of 0.05 M phosphate buffer dissolution medium at 37 ± 0.5 °C. Dissolution medium contains 0.1% Brij®35. Samples are removed at appropriate intervals. The content of the substances in the sample is determined using the RP-HPLC method for dual detection of SNAC and GLP-1 agonist. The content of a sample is calculated based on the peak area for the SNAC and GLP-1 agonist peaks in the chromatogram compared to the peak area values for the SNAC and GLP-1 agonist standards, respectively. The amount of SNAC and GLP-1 agonist released is calculated as a percentage of the actual content of the tablets, i.e. 100/200/300 mg SNAC/tablet and 3/5/4 mg GLP-1 agonist/tablet (eg analogue A, B or C). The actual content of the substances in the tablets is determined using analysis (II). The amount of GLP-1 agonist released is given as the average of 3 tablets.

Analysis II. Analysis of GLP-1 agonist and SNAC amounts

The tablets are weighed before extraction of the GLP-1 agonist and SNAC. The tablets are dissolved in the appropriate amount of 0.05 M phosphate buffer, pH 7.4, with 20% acetonitrile. An extraction time of two hours is used. The samples are centrifuged and a suitable volume is transferred to an HPLC vial. The appropriate GLP-1 and SNAC agonist standards are prepared using the same diluent used for the samples. To determine the content of GLP-1 agonist and SNAC, HPLC with a UV detector is used. The content of a sample is calculated based on the peak area for the SNAC and GLP-1 agonist peaks in the chromatogram compared to the peak area values for the SNAC and GLP-1 agonist standards, respectively.

Contents are given as the average value for 3 tablets.

Analysis III. Pharmacokinetic studies in Beagle dogs

Pharmacokinetic (PK) studies were conducted in Beagle dogs to determine exposure to GLP-1 agonists following oral administration of different dosage forms.

For pharmacokinetic studies, beagle dogs are used, 1-5 years old and weighing approximately 10-12 kg at the beginning of the study. The dogs are housed in groups in playpens (12-hour light: 12-hour dark cycle) and are fed individually and strictly once a day with Royal Canin medium-sized adult dog food (Royal Canin Products, subsidiary in China, or Brogaarden A/S, Denmark). Whenever possible, physical activity and social interaction in groups are allowed on a daily basis. Dogs are used for repeated pharmacokinetic studies using a suitable washout period between successive dosing administrations. Before starting the first pharmacokinetic study, provide an appropriate acclimatization period. All handling, dosing and collection of animal blood samples is performed by trained and qualified personnel. Before testing, dogs were fasted overnight and for 0 to 4 hours after dosing. In addition, dogs had limited access to water from 1 hour before dosing until 4 hours after dosing, but were allowed ad libitum access to water for the remainder of the period.

GLP-1 agonist tablets used for p.o. The studies described herein are SNAC-based immediate-release tablets administered orally.

Tablets containing a GLP-1 agonist are administered as follows: over 10 min. prior to tablet administration, dogs are injected subcutaneously with approximately 3 nmol/kg SEQ ID NO: 3). GLP-1 tablets are placed in the back of the dog's mouth to prevent chewing. Then the oral cavity is closed and 10 ml or 50 ml of tap water is injected using a syringe or probe to facilitate swallowing the tablet.

Collection of blood samples

Blood samples are collected at predetermined time points up to 10 hours after administration to adequately capture the full absorption profile, plasma concentration versus time, of the GLP-1 agonist.

At each blood sample collection time, approximately 0.8 mL of whole blood is collected into a 1.5 mL EDTA-coated tube and the tube is gently swirled to ensure mixing of the sample with the EDTA. Blood samples (eg 0.8 ml) are collected in EDTA buffer (8 mM) and then centrifuged at 4°C and 2000 G for 10 minutes. Blood plasma is pipetted into Micronic tubes on dry ice and kept at -20°C until analysis.

Blood samples are collected depending on the circumstances, for example from a venflon placed in the saphenous vein of the forearm on the forearm, during the first 2 hours and then using a syringe from the jugular vein at the remaining times (drain the first few drops from the venflon to remove the saline solution heparin from samples obtained from venflon).

Common Methods for Obtaining Pills

Method 1. Dry granulation

Dry granulation is carried out by rolling on a Gerteis MICRO-PACTOR. The roller speed is set to 1 rpm and the compaction intensity to 6 kN/cm, while the filling depth is 8 mm. After dry granulation, the tapes are manually sifted to obtain granules using a wire sieve with a mesh size of 0.8 mm. Optionally, a second stage of screening on a Retch vibrating screen, a 90 micron screen, is used to remove fine particles.

Method 2. Obtaining tablets

Tablets are produced on a Kilian Style One or Fette 102I equipped with one or four sets of punches that produce 4 mm round, 7 mm round or 5.75 x 10 mm, 7.2 x 12 mm, 7.5 x 12 mm, 7. 5 x 12.5 mm or 9 x 18 mm oval tablets. The punch size is selected according to the total weight of the tablet. In the case of the Kilian Style One, the press speed is set to 10%, and in the case of the Fette 102I, the press speed is set to 20 rpm. The fill volume is adjusted to produce tablets with target weights ranging from 28.6 mg to 823.5 mg. Compressive force values of from about 2 to 15 kN are used to produce tablets with a crushing strength of about 20 to 160 N, depending on the tablet size.

Examples

Example 1: Retrieving compositions

Tablets containing varying amounts of GLP-1 agonist, SNAC, and additional excipients were prepared. The content of substances in the resulting compositions is presented in Table 1 (Table 1.1, Table 1.2 and Table 1.3). The GLP-1 agonist A is semaglutide, the GLP-1 agonist B is diacylated [Aib8,Arg34,Lys37]GLP-1(7-37) (Example 2 of WO2011/080103), and the GLP-1 agonist C is diacylated -[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]GLP-1(7-37)-peptidyl-Glu-Gly (example 31 from WO2012/140117). Semaglutide can be prepared in accordance with the method described in WO2006/097537, example 4. GLP-1 agonists B and C can be prepared as described in WO2011/080103 and WO2012/140117, respectively. SNAC was prepared according to the method described in WO2008/028859.

Reference compositions A, B and C were generally prepared as described in WO2013/139694. The test compositions (A1, A2, B1-B4, C1 and C2) were generally prepared as described in Methods 1 and 2 above, with minor variations in the method prior to rolling and tabletting as indicated below.

Table 1. Tablet compositions expressed as mg per tablet

Composition Standard A A1 A2 GLP-1 Agonist A (mg) 3 3 3 SNAC (mg) 300 100 300 Magnesium stearate (mg) 9.7 2.6 7.7 Povidone (mg) 8 - - MCC (mg) 80 - -

Table 1.1. Review of compositions with GLP-1 A agonist

Composition Standard B B1 B2 B3 B4 GLP-1 agonist B (mg) 5 5 5 5 5 SNAC (mg) 300 100 200 300 300 Magnesium stearate (mg) 9.7 2.6 5.1 7.7 - Glyceryl dibehenate (mg) - - - - 2.2 Povidone (mg) 8 - - - - MCC (mg) 80 - - - -

Table 1.2. Review of compositions with GLP-1 B agonist

Composition of ingredients Standard C C1 C2 GLP-1 C agonist (mg) 4 4 4 SNAC (mg) 300 100 300 Magnesium stearate (mg) 9.7 2.6 7.7 Povidone (mg) 8 - - MCC (mg) 80 - -

Table 1.3. Review of compositions with GLP-1 C agonist

To prepare test compositions A1, A2, B1, B3, C1 and C2, the following procedure was followed: magnesium stearate granules were passed through a sieve of 355 μm or less. The correct amount of magnesium stearate and SNAC were weighed. Magnesium stearate was manually mixed with SNAC according to the geometric mixing principle. Two geometric dilution cycles were used. The remaining amount of SNAC was transferred to a mixing container and mixed with the SNAC and magnesium stearate premix for 30 minutes. at 25 rpm in the Turbula mixer. The mixture was rolled as described in method 1.

The correct amount of GLP-1 agonist and SNAC and magnesium stearate beads were weighed. The SNAC and magnesium stearate granules were added to the mixing container and manually mixed with the GLP-1 agonist according to the principle of geometric mixing. Two geometric dilution cycles were used. The remaining amount of SNAC and magnesium stearate granules was transferred to a mixing container. Final mixing of the GLP-1 agonist and beads was performed for 7 min. at 25 rpm or within 20 minutes. at 25 rpm in the Turbula mixer. Tablets were prepared from this composition in accordance with method 2.

B2 was prepared as follows: Magnesium stearate granules and SNAC were prepared as described for the previous compositions tested. The correct amount of SNAC and magnesium stearate and GLP-1 agonist beads were weighed. 1/3 of the SNAC and magnesium stearate granules were mixed with the GLP-1 agonist by adding the granules to the mixing container according to the principle of geometric mixing. Stirring was used for 7 minutes. at 25 rpm in the Turbula mixer. Two geometric dilution cycles were used. The remaining amount of SNAC and magnesium stearate granules was transferred to a mixing container and mixed according to the principle of geometric mixing. Final mixing of the GLP-1 agonist and beads was performed for 7 min. at 25 rpm in the Turbula mixer. Tablets were prepared from this composition in accordance with method 2.

B4 was prepared as follows: SNAC granules (without magnesium stearate) were prepared as described for the previous test compositions and in Method 1. The correct amount of GLP-1 agonist and SNAC granules were weighed. SNAC beads were added to a mixing container and mixed with the GLP-1 agonist according to the principle of geometric mixing. Two geometric dilution cycles were used. The remaining amount of SNAC pellets was added to the mixing container. Mechanical mixing of the GLP-1 agonist and beads was performed for 7 min. at 25 rpm in the Turbula mixer. Glyceryl dibehenate (Compritol 888 ATO) was passed through a sieve of 350 μm or less. The correct amount of glyceryl dibehenate was weighed. Glyceryl dibehenate was manually mixed with a mixture of SNAC beads and GLP-1 agonist according to the principle of geometric mixing. Three geometric dilution cycles were used. The resulting mixture was transferred to a container for mixing with the remaining mixture of SNAC beads and GLP-1 agonist. Final mixing with Compritol 888 ATO was carried out for 2 minutes. at 25 rpm in the Turbula mixer. Tablets were prepared from this composition in accordance with method 2.

Example 2 Solubility Test

The purpose of this study was to evaluate the solubility of a series of tablet formulations described in Example 1.

Solubility was measured according to Assay I. Table 2 shows the results for tablets prepared in accordance with Example 1 above, where the release is represented as "GLP-1 agonist in solution (%)" describing the amount of GLP-1 agonist in solution after 15 , 30 and 60 min. compared to the total amount of GLP-1 agonist in the tablet at the beginning of the experiment. The total amount of GLP-1 agonist and SNAC in the tablets was determined according to Assay II.

Table 2. GLP-1 agonist in solution (%)

Composition/dosage form GLP-1 agonist in solution (%) 15 minutes. 30 min. 60 min. A1 91.3 90.5 90.5 A2 89.0 96.8 95.8 B1 96.9 97.1 96.7 B2 89.3 89.7 90.0 B3 complete release complete release complete release B4 92.4 95.3 94.3 C1 98.2 97.6 97.5 C2 97.7 complete release complete release Standard A 35.5 58.1 75.6 Standard B 44.0 69.2 83.5 Standard C 44.9 71.4 93.1

The results obtained indicate that the tested compositions exhibit faster release of GLP-1 agonist compared to that observed for the reference compositions. Significantly faster release of GLP-1 agonist is observed at earlier time points, i.e. at 15 and 30 minutes. The difference in release is less significant after 60 minutes. The amount of SNAC in the tablets did not affect the release of the GLP-1 agonist, i.e. tablets containing 100 mg SNAC dissolve at the same rate as tablets containing 300 mg SNAC when measured after 15 minutes or later.

Additional data obtained after 5, 10, 15, 20, 30, 45 and 60 minutes for composition A1 and reference A are shown in figure 1, demonstrating the increased release at each time point.

Example 3 Oral Exposure

The purpose of the present study was to evaluate the exposure of a series of compositions described in Example 1 above when administered orally to Beagle dogs using 10 ml of water to dose the dogs. The number of tests performed for each formulation is indicated by n.

Analysis and results

Plasma concentrations of the corresponding GLP-1 agonist were analyzed using ELISA or a similar antibody assay such as LOCI. Individual plasma concentration-time profiles were analyzed using a non-compartmental model in WinNonlin v. 5.0 or Phoenix v. 6.2 or 6.3 (Pharsight Inc., Mountain View, California, USA) or other suitable PK analysis software.

Compound exposure measured at t=30 min was determined and normalized as dose/kg body weight.

The area under the plasma concentration versus time curve during the first 30 minutes was calculated. (AUC, [time x concentration]) (using Pharsight software) after oral administration and normalized as ((dose/kg body weight)*100) to obtain dose-adjusted exposure. The obtained average values are presented in Table 3.1.

The average dose-adjusted exposure of analogues A, B and C for t=0.5, 10, 15, 20 and 30 min obtained for formulations A1, reference A, B1 and reference B, C1 and reference C are shown in Figure 2 .

Because individual GLP-1 agonists behave differently, e.g. may have higher or lower overall bioavailability, it may also be appropriate to compare relative exposures to understand the effect of a particular dosage form/dose unit compared to the effect of another dosage form/dose unit containing the same GLP-1 agonist. Such results are included in Table 3.2, which shows that for each GLP-1 agonist, a 2-fold increase in exposure was obtained during the first 30 minutes with the dosage form disclosed herein compared to the reference dosage form.

Table 3.1. Dose adjusted exposure - average values

GLP-1 agonist Compound/
dosage form Number of SNACs Dose-adjusted AUC 0-30 min. (conventional units) Dose-adjusted exposure t=30 min. (kg/l) A (n=24) Standard A 300 1.68 0.104 A (n=16) A1 100 3.84 0.181 A (n=16) A2 300 2.63 0.153 B (n=24) Standard B 300 3.16 0.173 B (n=16) B1 100 6.86 0.297 B (n=16) B3 300 6.80 0.390 B (n=16) B4 300 6.71 0.385 C (n=12) Standard C 300 3.63 0.189 C (n=12) C1 100 9.02 0.442

Table 3.2. Dose adjusted exposure - relative exposure

GLP-1 agonist Compound Number of SNACs Fold change in dose-adjusted AUC 0-30 min normalized to reference Fold change in dose-adjusted exposure t=30 min, normalized relative to the standard A (n=24) Standard A 300 1.00 1.00 A (n=16) A1 100 2.29 1.74 A (n=16) A2 300 1.57 1.47 B (n=24) Standard B 300 1.00 1.00 B (n=16) B1 100 2.17 1.72 B (n=16) B3 300 2.15 2.25 B (n=16) B4 300 2.12 2.22 C (n=12) Standard C 300 1.00 1.00 C (n=12) C1 100 2.49 2.33

Example 4 Oral Exposure of 25-800 mg SNAC Tablets

Additional tablets with reduced and increased amounts of SNAC were prepared as described above for A1 and A2.

A5 had the same composition as A2 above. In this case, the granules were produced by dry granulation using MINI-PACTOR®, followed by removal of fine particles using a 90 µm sieve. Before dry granulation, SNAC and magnesium stearate were mixed for 50 minutes. at 25 rpm in a V-shell mixer. SNAC and magnesium stearate granules were mixed with the GLP-1 agonist for 10 min. at 25 rpm in a V-shell mixer before compressing the tablets according to Method 2. For Formulation A7, the GLP-1 agonist A was dry granulated with SNAC and magnesium stearate using MINI-PACTOR®, followed by removal of fines using a mesh size screen 90 microns. SNAC and magnesium stearate were mixed for 50 minutes. at 25 rpm in a V-shell mixer, and then GLP-1 was added and mixed for 20 minutes. at 25 rpm before dry granulation. The granules were further compressed into tablets according to method 2. The MINI-PACTOR was operated at a compaction intensity of 6 kN/cm, a gap of 1 mm, and a roller speed of 3 rpm. and using a wire screen with a mesh size of 0.63 μm in the case of both compositions A5 and A7.

Table 4.1. Tablet compositions expressed as mg per tablet

Composition Standard A A3 A4 A5 A6 A7 GLP-1 Agonist A (mg) 3 3 3 3 3 3 SNAC (mg) 300 25 100 300 800 300 Magnesium stearate (mg) 9.7 0.6 2.6 7.7 20.5 7.7 Povidone (mg) 8 - - - - - MCC (mg) 80 - - - - -

The purpose of this study was to evaluate the exposure of a series of formulations described in Table 4 when administered orally to Beagle dogs. Oral exposure was assessed in Beagle dogs as described in Example 1 above, using 50 ml of water to dose the dogs. The number of tests performed for each formulation is indicated by n.

The results were analyzed as described in Example 3 and the resulting average values are presented in Table 4.2 and the relative values are presented in Table 4.3 below.

Table 4.2. Dose adjusted exposure - average values

GLP-1 agonist Compound/
dosage form Number of SNACs Dose-adjusted AUC 0-30 min. (conventional units) Dose-adjusted exposure t=30 min. (kg/l) A (n=19) Standard A 300 0.82 0.048 A (n=16) A3 25 4.30 0.168 A (n=34) A4 100 3.30 0.151 A (n=16) A5 300 3.27 0.173 A (n=16) A6 800 2.48 0.147 A(n=16) A7 300 2.60 0.141

Table 4.3. Dose adjusted exposure - relative exposure

GLP-1 agonist Compound/
dosage form Number of SNACs Fold change in dose-adjusted AUC 0-30 min normalized relative to reference Fold change in dose-adjusted exposure t=30 min, normalized relative to the standard A (n=19) Standard A 300 1.00 1.00 A (n=16) A3 25 5.24 3.50 A (n=34) A4 100 4.02 3.15 A (n=16) A5 300 3.99 3.60 A (n=16) A6 800 3.02 3.06 A (n=16) A7 300 3.17 2.94

The data confirmed that an increase in exposure during the first 30 minutes was observed with the dosage form disclosed herein compared to the reference dosage form

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LIST OF SEQUENCES

<110> Novo Nordisk A/S

<120> SOLID COMPOSITIONS CONTAINING GLP-1 AGONIST AND N-(8-(2-HYDROXYBENZOYL)AMINO)CAPRYLIC ACID SALTS

<130> 170097WO01

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Claims (25)

1. Pharmaceutical composition having GLP-1 activity, containing: a) 0.5-50 mg GLP-1 agonist, b) 20-800 mg N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt and c) 1-10 mg lubricant, wherein said lubricant is magnesium stearate or glyceryl dibehenate; wherein said N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is at least 95% w/w. excipients of the composition, wherein the GLP-1 agonist is semaglutide. 2. Pharmaceutical composition according to claim 1, where the lubricant is magnesium stearate. 3. Pharmaceutical composition according to claim 1 or 2, consisting of: a) semaglutide, b) salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and c) magnesium stearate. 4. Pharmaceutical composition according to any of the previous paragraphs, where the composition contains 1-8 mg, such as 2-5 mg or such as 2-3 mg, magnesium stearate per 100 mg of said salt N-(8-(2 -hydroxybenzoyl)amino)caprylic acid. 5. The pharmaceutical composition according to any of the previous claims, wherein the N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). 6. Pharmaceutical composition according to any of the previous paragraphs, where the dose unit contains: a) 0.5-20 mg semaglutide, b) 50-400 mg SNAC and c) 1-10 mg magnesium stearate. 7. Pharmaceutical composition according to any of the previous paragraphs, where the dose unit contains: a) 1-10 mg semaglutide, b) 50-300 mg SNAC and c) 1-10 mg magnesium stearate. 8. The pharmaceutical composition according to any of the preceding claims, wherein the composition is a solid composition such as a tablet for oral administration. 9. Pharmaceutical composition according to any of the previous paragraphs for use in a method for treating diabetes mellitus and/or obesity. 10. A method of treating diabetes mellitus and/or obesity in a subject in need thereof, wherein the method comprises administering to said subject a therapeutically active amount of a composition according to any of the preceding claims.

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